DK168624B1 - Process for Preparation of 5-Chloro-2-Methoxynicotinic Acid by Chlorination of 2-Methoxynicotinic Acid - Google Patents

Abstract

A novel process for chlorinating 2-methoxynicotinic acid at the 5-position of the molecule is disclosed. The process involves the use of an alkali metal hypochlorite as the chlorinating agent in a homogeneous aqueous solvent system. The compound so produced, 5-chloro-2-methoxynicotinic acid, is known to be useful as an intermediate leading to various oral hypoglycemic agents of the benzenesulfonylurea class.

Description

in DK 168624 B1

This invention relates to a particular process for preparing 5-chloro-2-methoxynicotinic acid by chlorinating 2-methoxynicotinic acid at the 5-position of the molecule. The 5-chloro-2-methoxynicotinic acid produced is a known compound which is known to be of value as an intermediate in the preparation of certain benzenesulfonylurea compounds which are oral hypoglycemic agents.

In the past, 5-chloro-2-methoxynicotinic acid has been prepared by chlorination of 2-methoxynicotinic acid with chlorine in accordance with the procedure described by D.E. Kuhla et al. in U.S. Patent No. 3,879,403. However, this process involves the use of chlorine gas with the associated risks and the use of an aqueous solvent system which leads to heterogeneous reaction conditions with the resulting disadvantages.

In the search for improved methods of chlorination in this particular area, little is known about the use of other chlorinating agents for introducing 20 chlorine into the pyridine ring, although these agents have been used with varying success in the field of non-heterocyclic chemistry. For example, alkali metal hypochlorite solutions have previously been used to chlorine nitroparaffins within a certain defined pH range (e.g., pH 10-14) according to the method described by J.B. Tindall in US Patent No. 2 365 981, while similar solutions have also been used in the chlorination of p-hydroxybiphenyl to form 3-chloro-4-hydroxybiphenyl according to the process described by E.F. Grether in U.S. Pat.

1 832 484.

In accordance with the present invention, it has now been found possible to selectively chlorine 2-methoxy-nicotinic acid at the 5-position of the molecule and thus obtain 5-chloro-2-methoxynicotinic acid in pure form and in high yield using an alkali metal hypochlorite as chlorine - DK 168624 B1 2 solvent in an aqueous solvent sy stem.

The process of the invention is characterized in that 2-methoxynicotinic acid is subjected to the chlorinating action of an alkali metal hypochlorite in a homogeneous aqueous solvent system at a temperature in the range of about 10 to about 30 ° C until the chlorination reaction is substantially complete.

In this way, 2-methoxynicotinic acid is easily and directly converted to 5-chloro-2-methoxynicotinic acid without the aforementioned disadvantages associated with the use of gaseous chlorine.

In the process of the invention, the ratio of the 2-methoxynicotinic starting material to the alkali metal hypochlorite reagent used as the chlorinating agent is usually in the range of about 1.0: 1.0 to about 1.0: 6.0, the preferred range being from about 20 1.0: 1.2 to about 1.0: 2.0 to produce the desired chlorination at the 5-position of the molecule. Preferred reaction conditions consist in carrying out the reaction at about room temperature for a period of at least about 30 minutes. 16 hours. Although any alkali metal hypochlorite, such as lithium, sodium or potassium hypochlorite, can be used in the process, the preferred reagent is sodium hypochlorite. As a result, it has been found most convenient to carry out the reaction in a dilute aqueous sodium hypochlorite solution, e.g. a 5.25% aqueous solution of sodium hypochlorite which can be obtained comes cially under the trade name "Clorox". Upon completion of the reaction, the desired product, 5-chloro-2-methoxynicotinic acid, is readily recovered from the reaction mixture by simple acidification and filtration or by acidification and extraction with a suitable solvent such as chloroform, if necessary, followed by further purification by tearing with an appropriate solvent usually used for these purposes (eg hexane).

As previously stated, the product of the process of the invention, namely 5-chloro-2-methoxynicotinic acid, is a known compound which serves as a valuable intermediate which ultimately leads to certain benzenesulfonylurea compounds which are oral hypoglycemic agents which are described and patented by DE Kuhla et al. U.S. Patent No. 3,879,403. More specifically, 5-chloro-2-methoxynicotinic acid is first converted to 5-chloro-2-methoxy-nicotinoyl chloride, which is then converted to 4- [2- (5-chloro-2-methoxynicotinamido) ethyl] benzenesulfonamide, eventually giving 1-cyclohexyl-3- {4- [2- (5-chloro-2-methoxynico-tinamido) ethyl] benzenesulfonyl} urea or 1- (bicyclo [2.2.1]) hept-5-en-2-yl-endo-methyl) -3- {4- [2- (5-chloro-2-methoxynicotinamido) ethyl] benzenesulfonyl} urea or 1- (4-chlorocyclohexyl) -3- {4 - [2- (5-chloro-2-methoxynicotinamido) ethyl] benzenesulfonyl} urea by the known multi-step method previously described by DE

Kuhla et al. in the aforementioned US patent.

Thus, the novel process of the invention now provides the valuable intermediate, 5-chloro-2-methoxynicotinic acid, in pure form and in high yield 25 by a peculiar selective 1-step chlorination method which represents a greater improvement over the prior art. given the ease of the synthesis and greatly reduced costs. More specifically, it avoids the use of chlorine gas and the associated risks and allows the reaction to be carried out under normal homogeneous reaction conditions, avoiding unmanageable and cumbersome suspensions.

Preparation A 35

A stirred slurry consisting of 35 g (0.22 mol) of 2-chloronicotinic acid (available from Lonza Inc., Fair Lawn, 4 DK 168624 B1

New Jersey, USA) in 400 ml of methanol was treated with 25.4 g (0.47 mole) of sodium methyl at which was added portionwise. Stirring was then continued until a clear solution was obtained. At this point, the liquid reaction mixture was transferred to a steel autoclave and heated to 125 ° C for about 16 hours (i.e. overnight). After completing this step, the reaction mixture was cooled to room temperature (about 20 ° C), filtered and the filter cake washed with methanol. The combination of organic filtrate and methanol washing solutions was then concentrated in vacuo to give a white solid which was then dissolved in water. The aqueous solution was then adjusted to pH 3.0 with 6N hydrochloric acid and immediately filtered to remove 15 (i.e., recover) the precipitated solid which was then air dried to constant weight for about 16 hours (i.e. overnight). ). In this way, 21.8 g (64%) of pure 2-methoxynicotinic acid was finally obtained, m.p. 147-148 ° C (literature mp 144-146 ° C, according to D.E. Kuhla et al. In U.S. Patent No. 3,879,403). The pure product was further characterized by magnetic-nuclear-sonance data.

Example 1 25

A sample of 306 mg (0.002 mol) of 2-methoxynicotinic acid (the product of Preparation A) was added in a portion to 20 ml of well stirred aqueous 5.25% sodium hypochlorite solution ("Clorox"). The resulting mixture (now a solution) was then stirred at room temperature (about 20 ° C) for about 18 hours (i.e. overnight). After completion of this step, the reaction mixture was acidified with 10 ml of 1 N hydrochloric acid and the resulting precipitate was then extracted with chloroform. The organic extracts were combined, dried over anhydrous magnesium sulfate and filtered and the filtrate was then concentrated in vacuo to give 195 mg (52%) of pure 5-chloro-2-methoxynicotinic acid, m.p. 139-141 ° C (literature mp 149-150 ° C, according to D.E. Kuhla et al. In U.S. Patent No. 3,879,403). The pure product was further characterized by magnetic-nuclear resonance data and mass spectroscopy.

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Example 2

A sample of 217 g (1.42 mol) of 2-methoxynicotinic acid (the product of Preparation A) was added portionwise to 2.5 10 liters of well stirred aqueous 5.25% sodium hypochlorite solution ("Clorox") at 10 ° C, sufficient cooling was maintained throughout the course of the addition to keep the reaction mixture temperature below 28 ° C. After completing this step, the reaction mixture was stirred at room temperature (about 20 ° C) for about 16 hours (i.e., overnight) and then acidified to pH 2.0 with concentrated hydrochloric acid. The precipitated solid product was collected by suction filtration and then triturated with two 500 ml portions of hexane followed by drying under high vacuum to give 201 g (75%) of pure 5-chloro-2-methoxynicotinic acid. This product was identical in every respect to the product of Example 1, as confirmed especially by magnetic-nuclear resonance data.

Example 3 A 12 liter aqueous 5.25% sodium hypochlorite solution ("Clorox") solution was placed at 10 ° C. in a 22 liter three-necked, round bottom flask equipped with a thermometer, mechanical stirrer, and vented. g (5.66 mole) of 2-methoxynicotinic acid to the stirred solution over 75 minutes, maintaining sufficient cooling throughout the course of the addition to keep the reaction mixture temperature below 30 ° C. After completion of this step, the resulting white slurry became at 21 ° C treated with an additional 4 liters of fresh aqueous 5.25% sodium hydrochloric acid solution ("Clorox") to bring the pH of the reaction mixture to about pH 7.0. The latter mixture was then stirred at room temperature for 1 hour. The resulting light brown slurry 5 was then treated with 3.5 liters of chloroform and the pH was adjusted to about 1.5 by the addition of conc. enteric hydrochloric acid, followed by further dilution with 5.2 liters of chloroform. The separated chloroform layer was then filtered and stored, while the aqueous layer 10 was extracted with 3.5 liters of fresh chloroform. The combined organic layers were then washed once with 4 liters of 10% aqueous hydrochloric acid and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration and the solvent by evaporation under reduced pressure, a yellowish-white solid was obtained, which was then triturated with 3 liters of hexane and filtered. The resulting almost white solid was then washed with a liter of fresh hexane on the filter funnel and air dried to constant weight for about 16 hours, finally giving 782.4 g (73%) of pure 5-chloro-2-methoxynicotinic acid, m.p. 137-138 ° C. This product was identical in every respect to the product of Example 1, as confirmed in particular by magnetic nuclear resonance data.

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Claims (6)

Process for the preparation of 5-chloro-2-methoxy-nicotinic acid by chlorination of 2-methoxynicotinic acid, characterized in that 2-methoxynicotinic acid is exposed to the chlorinating effect of an alkali metal hypochlorite in a homogeneous aqueous solvent system at a temperature in the region from about 10 to about 30 eC, 10 until the chlorination reaction is substantially complete. Process according to claim 1, characterized in that the alkali metal hypochlorite 15 used as a reagent is sodium hypochlorite. Process according to claim 2, characterized in that the molar ratio of the 2-methoxynicotinic acid starting material to the sodium hypochlorite reagent is in the range from about 1.0: 1.0 to about 1.0: 6.0. Process according to claim 3, characterized in that the molar ratio is in the range from about 1.0: 1.2 to about 1.0: 2.0. 25 Process according to any one of the preceding claims, characterized in that the reaction is carried out at room temperature for at least approx. 16 hours. Process according to any one of the preceding claims, characterized in that the 5-chloro-2-methoxynicotinic acid produced is recovered from the reaction mixture. 35